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Species-specific differences in the glucocorticoid receptor transactivation function upon binding with
Kiyoshi Tanigawa1, Hideki Nagase, Koichi Ohmori
1Pharmacobioregulation Research Laboratory, Hanno Research Center, Taiho Pharmaceutical Co, Ltd, Saitama, Japan. k-tanigawa@taiho.co.jp
International Immunopharmacology
|August 22, 2002
Summary
Species-specific differences in glucocorticoid receptor (GR) activity were observed. Esterified-betamethasone showed reduced transactivation in rats, correlating with fewer side effects in an asthma model.
Area of Science:
- Pharmacology
- Molecular Biology
- Immunology
Background:
- Glucocorticoids (GCs) are potent anti-inflammatory drugs but have limiting side effects.
- Dissociating GR transactivation and transrepression is a therapeutic goal to separate efficacy from side effects.
Purpose of the Study:
- To investigate species-specific differences in glucocorticoid receptor (GR) transactivation and transrepression activities.
- To determine if these differences can be exploited to reduce GC-induced side effects.
Main Methods:
- Reporter assays in CV-1 cells transfected with human or rat GR to assess transactivation and transrepression.
- Enzyme induction assay (tyrosine aminotransferase) in rat hepatoma H4-II-E cells.
- In vivo assessment of side effects (thymus involution, body weight loss) in a rat asthma model.
Main Results:
- Dexamethasone (DEX), betamethasone (BM), and their esterified derivatives exhibited full transrepression in both human and rat GR assays.
- Esterified-BM demonstrated partial transactivation with rat GR, unlike human GR, BM, or esterified-DEX.
- Esterified-BM failed to induce tyrosine aminotransferase in rat cells and showed minimal side effects in rats, despite similar receptor binding affinities across species.
Conclusions:
- Species-specific differences in GR transactivation potency exist, particularly for esterified-BM.
- These differences are not attributable to receptor binding affinity variations.
- Targeting species-specific GR transactivation may offer a strategy to develop safer anti-inflammatory glucocorticoids.